Much effort has been expended to find effective treatments and a cure to non-insulin dependent diabetes mellitus (NIDDM), also referred to as type II diabetes mellitus. In NIDDM, the body continues to produce insulin, however, the insulin is not as effective as it should be and glucose uptake by the muscles is inhibited (i.e., the body becomes resistant to the effect of insulin). Typically, NIDDM is controlled by diet, oral medication and eventually, by regular periodic insulin injection. In addition, because NIDDM generally has a long latent period in which the patient is asymptomatic, such patients are often afflicted by other disease states as a consequence of undetected NIDDM, such as atherosclerosis, by the time that the NIDDM symptoms become manifest.
Regular periodic insulin injections, while hailed as a breakthrough forty years ago, often adversely affect a diabetic patient's lifestyle and do not seem to prevent vascular complications. Accordingly, the search for less intrusive treatments has been ongoing. One area of research, for example, has been to reduce or delay glucose uptake within the small intestine, so as to moderate blood glucose levels. For example, Thompson et al., "Phytic acid and calcium affect the in vitro rate of navy bean starch digestion and blood glucose response in humans," Am. J. Clin. Nutr., 46:467-73 (1987), suggests that the addition of phytic acid to foods may be used to delay starch digestion and glycemic response, whereas the addition of calcium has an opposite effect. U.S. Pat. No. 4,952,568 to Sawai et al. is directed to methods for treating type II diabetes by administering phytic acid salts in amounts sufficient to moderate blood glucose levels. No effective clinical applications appear to have been developed from the foregoing research.
More recently, a number of studies have suggested an association between iron metabolism disorders, such as thalassemia and hemochromatosis, and a number of disease states, such as type II (non-insulin dependent) diabetes mellitus and atherosclerosis. For example, Matthews, et al., "Iron and Atherosclerosis: Inhibition by the Iron Chelator Deferiprone," J. of Surg. Res., 73:35-40 (1997) suggests that the iron chelator Deferiprone may be useful in reducing atherogenesis by serving as anti-oxidant, although the in-vivo results reported there were not statistically significant. Tuomainen et al., "Body Iron Stores Are Associated With Serum Insulin and Blood Glucose Concentrations," Diabetes Care, 20(3):426-428 (1997), conclude that mildly elevated body iron stores are associated with statistically significant elevations in glucose homeostasis.
In accordance with previously known methods, iron metabolism disorders, such as thalassemia or hemochromatosis have been treated using iron chelation therapy, typically using either Deferoxamine administered by timed intramuscular injection via a pump. More recently, the oral iron chelator Deferiprone has become clinically available, although such orally administered chelators do not appear to have the efficacy of injected drugs. Both of these drugs present toxicity issues that are outweighed only by their effectiveness in reducing body-iron stores. Neither drug is suitable for widespread use in patients not exhibiting effects of a serious iron metabolism disorder.
In view of the foregoing, it would be desirable to provide methods and compounds for lowering and controlling body iron stores to treat or cure disease states, such as NIDDM, certain types of primary hypertension, and atherosclerosis that may be significantly worsened by an otherwise normal amount of body iron.
It further would be desirable to provide methods and compounds for reducing iron absorption that have low toxicity and therefore may be used in large patient populations with little adverse impact.
It also would be desirable to provide methods and compounds that lower the risk of atherogenesis, and other disease states associated with high oxidative stress.
It still further would be desirable to provide methods and compounds for reducing and controlling iron body stores in a phased manner, wherein initial body iron stores are lowered to a desired level, and thereafter maintained at the desired level by reducing intestinal iron absorption using low-toxicity compounds.